1. Field of the Invention
This invention relates to a process for preparing 1-alkylimidazoles of high purity and in high yield.
2. Description of the Related Art
The alkylation of imidazoles at the 1-position by reaction with an alkyl halide is known in the prior art. U.S. Pat. No. 4,140,518 teaches that 2-alkyl imidazoles can be alkylated at the 1-position by reacting the imidazole and a 10% molar excess of alkyl halide in the presence of sodium hydroxide. The alkyl halide and imidazole are heated to 130.degree. C. for 30 minutes whereupon the sodium hydroxide is added and the temperature is then increased to 150.degree. C. and held there for 2 hours. The patent also teaches that the alkylation reaction can be accomplished in an inert, organic diluent which is preferably dimethylformamide. U.S. Pat. Nos. 4,525,475 and 4,328,234 teach that imidazoles can be alkylated at the 1-position using alkyl halide and an acid acceptor such as an alkali metal alkoxide in the absence of solvent. U.S. Pat. No. 4,282,238 teaches that imidazoles can be alkylated at the 1-position by reacting 1 mole of an alkyl halide with 2 moles of imidazole in such solvents as tetrahydrofuran and dioxane at 160.degree. C. for 15 hours in the absence of base and solvent. European Patent Application 0,066,884 teaches that 1-lauryl-2-methylimidazole can be made by heating 0.23 moles of 2-methylimidazole and 0.10 moles of lauryl bromide at 200.degree. C. for 10 hours in the absence of inorganic base and in the absence of solvent. Chemical Abstracts 70:11699f teaches that 1-dodecyl-2-methylimidazole can be made by dropping 1 mole of dodecyl chloride into a mixture comprised of 1 mole of 2-methylimidazole and 1 mole of sodium hydroxide at 140.degree.-150.degree. C. in the absence of solvent. Chemical Abstracts 89:109246y teaches that 1-alkylimidazoles can be prepared by adding the imidazole in tetrahydrofuran solution to a suspension of sodium hydride or t-butyl alcohol in tetrahydrofuran, refluxing for 4 hours, cooling, adding an alkyl halide, and refluxing for an additional 6 hours. Biochemical Pharmacology 23, 2377-2386 (1974) teaches that 1-hexylimidazole can be prepared in 68% yield by heating a mixture comprising 0.1 moles of imidazole and 0.12 moles of n-hexylbromide to reflux for 1 hour. The Journal of The American Chemical Society 93, 6584 (1971) teaches that 1-dodecylimidazole can be prepared by heating a mixture comprising equimolar quantities of imidazole and lauryl bromide at 150.degree. C. for 1 hour in the absence of base in the absence of solvent.
The reaction of imidazoles and alkyl halides is generally disclosed in U.S. Pat. No. 3,507,831 and in Chemical Abstracts 99:88113s, 91:157734u, 91:74616f, 82:4255c, 69:106622u.
The reaction of imidazoles and alkyl halides in the presence of phase transfer catalysts is generally disclosed in Chemical Abstracts 109:230887t, 102:131300v, 101:6977z, 99:87391u, 99:69862u, and 87:5864r. British Patent 1,122,717 teaches the alkylation of imidazoles with a molar excess of alkyl halide and a large excess of base in the presence of polar solvents such as alcohols or ketones which are at least partially water soluble. The use of these partially water soluble solvents leads to difficulties in an aqueous work up step which removes the excess base. British Patent 1,122,717 also teaches that no product is obtained from the attempted alkylation of imidazoles in non-polar solvents like toluene even in the presence of excess alkyl halide. Other disadvantages with the prior art processes include low product purity, poor yields, solvent losses during aqueous work up, and product purification steps. Contrary to the teachings of British Patent 1,122,717, surprisingly high yields of very pure product containing only small amounts of the 3-alkyl quaternary ammonium compound can be obtained by alkylating imidazoles in aromatic solvents when the alkyl halide is present in less than a 1:1 molar ratio of imidazole:alkyl halide.
None of the prior art processes combines the steps of the gradual addition of an alkyl halide to a slight molar excess of imidazole in a non-reactive aromatic solvent at temperatures of about 115.degree. C. or below. None of the prior art processes is conducive to scale up to a commercial process because they involve carrying out the reaction in the absence of solvent and/or carrying out the reaction at temperatures greater than 115.degree. C. or carrying out the reaction in solvents with unacceptable water solubilities. Many of the processes of the prior art produce a product containing unacceptable amounts of the quaternary ammonium product produced by double alkylation. The process of the present invention eliminates the problems encountered by the prior art processes by carrying out the reaction in non-polar solvents such as toluene or other non-reactive aromatic solvents using a deficiency of alkyl halide at a temperature of about 90.degree. C. Inorganic materials dissolved in the reaction solvent can be conveniently and easily extracted with water leaving a solution of substantially pure 1-alkylimidazole.